Chemical formula: C₂₁H₂₈O₂ Molecular mass: 312.446 g/mol PubChem compound: 13109
The precise mode of action of levonorgestrel as an emergency contraceptive is not known.
At the recommended regimen, levonorgestrel is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the preovulatory phase, when the likelihood of fertilisation is the highest. Levonorgestrel is not effective once the process of implantation has begun.
Intrauterine delivery system has mainly local progestogenic effects in the uterine cavity.
The high levonorgestrel concentration in the endometrium down-regulates endometrial oestrogen and progesterone receptors. The endometrium becomes relatively insensitive to the circulating estradiol and a strong antiproliferative effect is seen. Morphological changes of the endometrium and a weak local foreign body reaction are observed during use. Thickening of the cervical mucus prevents passage of the sperm through the cervical canal. The local milieu of the uterus and of the fallopian tubes inhibits sperm mobility and function, preventing fertilization. In clinical trials with intrauterine delivery system ovulation was observed in the majority of the subset of women studied. Evidence of ovulation was seen in 23 out of 26 women in the first year, in 19 out of 20 women in the second year and in all 16 women in the third year. In the fourth year, evidence of ovulation was observed in the one woman remaining in the subset and in the fifth year, no women remained in this subset.
Orally administered levonorgestrel is rapidly and almost completely absorbed.
The absolute bioavailability of levonorgestrel was determined to be almost 100% of the dose administered.
The results of a pharmacokinetic study carried out with 16 healthy women showed that following ingestion of one tablet of 1.5 levonorgestrel maximum drug serum levels of levonorgestrel of 18.5 ng/ml were found at 2 hours.
Levonorgestrel is bound to serum albumin and sex hormone binding globulin (SHBG). Only about 1.5% of the total serum levels are present as free steroid, but 65% are specifically bound to SHBG.
About 0.1% of the maternal dose can be transferred via milk to the nursed infant.
The biotransformation follows the known pathways of steroid metabolism, the levonorgestrel is hydroxylated by liver enzymes mainly by CYP3A4 and its metabolites are excreted after glucuronidation by liver glucuronidase enzymes.
No pharmacologically active metabolites are known.
After reaching maximum serum levels, the concentration of levonorgestrel decreased with a mean elimination half-life of about 26 hours.
Levonorgestrel is not excreted in unchanged form but as metabolites. Levonorgestrel metabolites are excreted in about equal proportions with urine and faeces.
A pharmacokinetic study showed that levonorgestrel concentrations are decreased in obese women (BMI ≥30 kg/m²) (approximately 50% decrease in Cmax and AUC0-24), compared to women with normal BMI (<25 kg/m²) (Praditpan et al., 2017).
Another study also reported a decrease of levonorgestrel Cmax by approximately 50% between obese and normal BMI women, while doubling the dose (3 mg) in obese women appeared to provide plasma concentration levels similar to those observed in normal women who received 1.5 mg of levonorgestrel (Edelman et al., 2016). The clinical relevance of these data is unclear.
Levonorgestrel is released locally into the uterine cavity. The in vivo release curve is characterized by an initial steep decline that slows down progressively resulting in little change after 1 year until the end of the intended 3-year period of use. Estimated in vivo delivery rates for different time points are provided in Table 3.
Table 3. Estimated in vivo release rates based on observed ex vivo residual content data:
| Time | Estimated in vivo release rate [micrograms/24 hours] |
|---|---|
| 24 days after insertion | 14 |
| 60 days after insertion | 10 |
| 1 year after insertion | 6 |
| 3 years after insertion | 5 |
| Average over 1st year | 8 |
| Average over 3 years | 6 |
Following insertion, levonorgestrel is released from the IUS into the uterine cavity without delay based on serum concentration measurements. More than 90% of the released levonorgestrel is systemically available. Maximum serum concentrations of levonorgestrel are reached within the first two weeks after insertion of IUS. Seven days after insertion, a mean levonorgestrel concentration of 162 pg/ml (5th percentile: 102pg/ml – 95th percentile: 249 pg/ml) was determined. Thereafter serum concentrations of levonorgestrel decline over time to reach mean concentrations of 59 pg/ml (5th percentile: 36pg/ml – 95th percentile: 92 pg/ml) after 3 years. With the use of a levonorgetrel-releasing intrauterine system, the high local drug exposure in the uterine cavity leads to a strong concentration gradient from the endometrium to the myometrium (gradient endometrium to myometrium >100-fold), and to low concentrations of levonorgestrel in serum (gradient endometrium to serum >1000-fold).
Levonorgestrel is bound non-specifically to serum albumin and specifically to SHBG. Less than 2% of the circulating levonorgestrel is present as free steroid. Levonorgestrel binds with high affinity to SHBG. Accordingly, changes in the concentration of SHBG in serum result in an increase (at higher SHBG concentrations) or in a decrease (at lower SHBG concentrations) of the total levonorgestrel concentration in serum. The concentration of SHBG declined on average by about 15% during the first month after insertion of IUS and remained stable over the 3 year period of use. The mean apparent volume of distribution of levonorgestrel is about 106 L.
Levonorgestrel is extensively metabolized. The most important metabolic pathways are the reduction of the ∆4-3-oxo group and hydroxylations at positions 2α, 1β and 16β, followed by conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of LNG. The available in vitro data suggest that CYP mediated biotransformation reactions may be of minor relevance for LNG compared to reduction and conjugation.
The total clearance of levonorgestrel from plasma is approximately 1.0 ml/min/kg. Only trace amounts of levonorgestrel are excreted in unchanged form. The metabolites are excreted in faeces and urine at an excretion ratio of about 1. The excretion half-life is about 1 day.
The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG which itself is influenced by oestrogens and androgens. A decrease of SHBG concentration leads to a decrease of total levonorgestrel concentration in serum indicating non-linear pharmacokinetics of levonorgestrel with regard to time. Based on the mainly local action of levonorgestrel IUS, no impact on the efficacy of IUS is expected.
In a one-year phase III study in post-menarcheal female adolescents (mean age 16.2, range 12 to 18 years) pharmacokinetic analysis of 283 adolescents showed estimated LNG serum concentrations slightly higher (approximately 10%) in adolescents compared to adults. This correlates to the generally lower body weight in adolescents. The ranges estimated for adolescents lie, however, within the ranges estimated for adults, showing high similarity.
No differences in the pharmacokinetics of LNG are expected between adolescents and adults following insertion of IUS.
A three-year phase III study in the Asian-Pacific region (93% Asian women, 7% other ethnicities) using IUS has been performed. A comparison of pharmacokinetic characteristics of LNG of the Asian population in this study with that of the Caucasian population from another phase III study showed no clinically relevant difference in systemic exposure and other pharmacokinetic parameters. In addition, the daily release rate of IUS was the same in both populations.
No differences in the pharmacokinetics of LNG are expected between Caucasian and Asian women following insertion of IUS.
Animal experiments with levonorgestrel have shown virilisation of female fetuses at high doses.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenicity potential.
Nonclinical data revealed no special hazard for humans based on studies of safety pharmacology, pharmacokinetics and toxicity, including genotoxicity and carcinogenic potential of levonorgestrel. Studies in monkeys with intrauterine delivery of levonorgestrel for 9 to 12 months confirmed local pharmacological activity with good local tolerance and no signs of systemic toxicity. No embryotoxicity was seen in rabbits following intrauterine administration of levonorgestrel. The safety evaluation of the elastomer components of the hormone reservoir, the polyethylene materials as well as the silver ring of the product, the silver profile and the combination of elastomer and levonorgestrel, based on both the assessment of genetic toxicology in standard in vitro and in vivo test systems and on biocompatibility tests in mice, rats, guinea pigs, rabbits and in vitro test systems have not revealed bio-incompatibility.
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